Links

Research & Scholarship

Current Research and Scholarly Interests

Dr. Dodd is involved in clinical trials using endovascular coils that have a fiber coating that help heal aneurysms of the neck and can prevent an aneurysm from reforming. He uses minimally invasive endoscopic techniques to treat brain tumors.

Dodd's research interests are in cerebral blood vessel reactivity and stroke.

Abstract

Objective: Metastatic disease to the sella is uncommon and there are limited available data regarding the clinical aspects of this disease. We sought to characterize the clinical demographics of sellar metastases.Methods: Retrospective chart review of adults at Stanford University Medical Center from 1980 to 2011 with metastatic disease to the sella.Results: 13 subjects were identified (9 F). The mean age at diagnosis was 55 years (range: 25-73 y). 6 (46%) had breast carcinoma, 3 (23%) had renal cell carcinoma, 2 (15%) had squamous cell carcinoma of the head and neck, 1 had bronchoalveolar carcinoma of the lung, and 1 had nodular sclerosing Hodgkin's lymphoma. The most common presenting signs and symptoms were headache (58%), followed by fatigue (50%), polyuria (50%), visual field defects (42%), and ophthalmoplegia (42%). 75% presented with at least one pituitary hormone insufficiency, including 6 (50%) with diabetes insipidus (DI). 8 (67%) subjects had secondary hypothyroidism, and 5 (45%) had secondary adrenal insufficiency. Of the patients with stalk involvement, 86% had DI. All patients had a prior diagnosis of malignancy for a mean duration of 95 months.Conclusion: In this retrospective review, the most common neoplastic sources to the sella were breast and renal cell carcinoma. Secondary hypothyroidism was the most common endocrine abnormality, followed by DI, and adrenal insufficiency. New onset central hypothyroidism and diabetes insipidus along with known malignancy in a patient with a sellar lesion should raise the suspicion of a metastatic source.

Abstract

: The safety of flow-diverting stents for the treatment of ruptured intracranial aneurysms is unknown.: A 35-year-old woman with a ruptured dissecting aneurysm of the intradural right vertebral artery and incorporating the right posterior inferior cerebellar artery was treated with a Pipeline Embolization Device (PED). Five days after reconstruction of the diseased right vertebral segment, she was treated for vasospasm, and retraction of the PED was observed, leaving her dissecting aneurysm unprotected. A second PED was placed with coverage of the aneurysm, but vasospasm complicated optimal positioning of the device.: In addition to the potential risks of dual antiplatelet therapy in these patients, this case illustrates 2 pitfalls of flow-diverting devices in vessels in vasospasm: delayed retraction of the device and difficulty positioning the device for deployment in the setting of vasospasm.: ANR, aneurysmPED, Pipeline Embolization DevicePICA, posterior inferior cerebellar arterySAH, subarachnoid hemorrhage.

Abstract

It is not uncommon that endovascular balloon test occlusion (BTO) is performed to assess collateral blood flow and risk of injury of permanent occlusion of the internal carotid artery (ICA). This case is the first reported of detection and reversal of the inferolateral trunk (ILT) syndrome in an awake patient during provocative BTO; prompt recognition of the syndrome effectively prevented permanent neurologic deficits.The case of a 42-year-old woman is reported who had a left sphenoid wing meningioma with extension into the cavernous sinus and who underwent awake catheter angiography with provocative BTO of the ICA. Serial examinations by intraoperative monitoring neurologists and neurointerventionalists detected acute progressive left retro-orbital pressure followed by sudden inability to adduct the left eye, or a left medial rectus palsy, indicative of the ILT syndrome which led to immediate balloon deflation and resolution of the deficits. The hypothesis was that hypoperfusion of the ILT, an arterial branch of the ICA which provides blood supply to several cranial nerves (CN) III, CN V1 and CN V2, caused her acute symptoms.Although cerebral ischemia is a well known complication of endovascular procedures, CN ischemia is a rare potential risk. Knowledge of cerebrovascular anatomy and serial examinations prevented neurologic deficits; this case underscores the added utility of examinations by intraoperative monitoring neurologists and interdisciplinary collaboration.

Abstract

Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ischaemic brain damage in human beings.For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12-95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov, number NCT00728182.Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment-12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38-0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42-0·83).Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials.NoNO Inc and Arbor Vita Corp.

Abstract

A pilot study was performed in patients with recurrent back pain after spinal fusion surgery to evaluate the ability of (18)F-NaF PET/CT imaging to correctly identify those requiring surgical intervention and to locate a site amenable to surgical intervention.In this prospective study 22 patients with recurrent back pain after spinal surgery and with equivocal findings on physical examination and CT were enrolled for evaluation with (18)F-NaF PET/CT. All PET/CT images were prospectively reviewed with the primary objective of identifying or ruling out the presence of lesions amenable to surgical intervention. The PET/CT results were then validated during surgical exploration or clinical follow-up of at least 15 months.Abnormal (18)F-NaF foci were found in 16 of the 22 patients, and surgical intervention was recommended. These foci were located at various sites: screws, cages, rods, fixation hardware, and bone grafts. In 6 of the 22 patients no foci requiring surgical intervention were found. Validation of the results by surgery (15 patients) or on clinical follow-up (7 patients) showed that (18)F-NaF PET/CT correctly predicted the presence of an abnormality requiring surgical intervention in 15 of 16 patients and was falsely positive in 1 of 16.In this initial investigation, (18)F-NaF PET/CT imaging showed potential utility for evaluation of recurrent symptoms after spinal fusion surgery by identifying those patients requiring surgical management.

Abstract

Cerebral vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage. Nicardipine has previously been used to treat vasospasm through superselective intracranial microcatheter injections.To evaluate a simple method of treatment of vasospasm with slow infusion of nicardipine from a cervical catheter.Twenty-seven patients with symptomatic vasospasm were treated over 4 years with cervical catheter infusions. Nicardipine was infused at 20 mg/h for 30 to 60 minutes. Angioplasty was used in severe cases at the operator's discretion. Outcome at discharge and follow-up was evaluated with Glasgow Outcome Scale.Twenty-seven patients (17 women, 12 men) received intra-arterial therapy for vasospasm. Vasospasm treatment was done at a mean post-hemorrhage date of 7.2 days (range, 4-15 days). They underwent 48 sessions of treatment (mean, 1.8 per patient) in 72 separate arterial territories. Twelve patients underwent multiple treatments. The mean dose used per session was 19.2 mg (range, 5-50 mg). Four patients underwent angioplasty for severe vasospasm. Twenty-two patients (81.5%) had clinical improvement after the infusion. Angiographic improvement was seen in 86.1% of the vessels analyzed, which had moderate or severe spasm before infusion. Overall, 17 patients (62.9%) had good outcome (Glasgow Outcome Scale score, 4 and 5) at discharge, 11 had poor outcome, and 1 patient died. Follow-up was available in 19 patients, and 18 were doing well (Glasgow Outcome Scale score, 4 and 5).Intra-arterial nicardipine is an effective and safe treatment for cerebral vasospasm. In most patients, infusion can be performed from the cervical catheter, with microcatheter infusion and angioplasty reserved for the more severe and resistant cases.

Abstract

Grade III arteriovenous malformations (AVMs) are diverse because of their variations in size (S), location in eloquent cortex (E), and presence of central venous drainage (V). Because they may have implications for management and outcome, the authors evaluated these variations in the present study.Between 1984 and 2010, 100 patients with Grade III AVMs were treated. The AVMs were categorized by Spetzler-Martin characteristics as follows: Type 1 = S1E1V1, Type 2 = S2E1V0, Type 3 = S2E0V1, and Type 4 = S3E0V0. The occurrence of a new neurological deficit, functional status (based on modified Rankin Scale [mRS] score) at discharge and follow-up, and radiological obliteration were correlated with demographic and morphological characteristics.One hundred patients (49 female and 51 male; age range 5-68 years, mean 35.8 years) were evaluated. The size of AVMs was less than 3 cm in 28 patients, 3-6 cm in 71, and greater than 6 cm in 1; 86 AVMs were located in eloquent cortex and 38 had central drainage. The AVMs were Type 1 in 28 cases, Type 2 in 60, Type 3 in 11, and Type 4 in 1. The authors performed embolization in 77 patients (175 procedures), surgery in 64 patients (74 surgeries), and radiosurgery in 49 patients (44 primary and 5 postoperative). The mortality rate following the management of these AVMs was 1%. Fourteen patients (14%) had new neurological deficits, with 5 (5%) being disabling (mRS score > 2) and 9 (9%) being nondisabling (mRS score ? 2) events. Patients with Type 1 AVMs (small size) had the best outcome, with 1 (3.6%) in 28 having a new neurological deficit, compared with 72 patients with larger AVMs, of whom 13 (18.1%) had a new neurological deficit (p < 0.002). Older age (> 40 years), malformation size > 3 cm, and nonhemorrhagic presentation predicted the occurrence of new deficits (p < 0.002). Sex, eloquent cortex, and venous drainage did not confer any benefit. In 89 cases follow-up was adequate for data to be included in the obliteration analysis. The AVM was obliterated in 78 patients (87.6%), 69 of them (88.5%) demonstrated on angiography and 9 on MRI /MR angiography. There was no difference between obliteration rates between different types of AVMs, size, eloquence, and drainage. Age, sex, and clinical presentation also did not predict obliteration.Multimodality management of Grade III AVMs results in a high rate of obliteration, which was not influenced by size, venous drainage, or eloquent location. However, the development of new neurological deficits did correlate with size, whereas eloquence and venous drainage did not affect the neurological complication rate. The authors propose subclassifying the Grade III AVMs according to their size (< 3 and ? 3 cm) to account for treatment risk.

Abstract

Moyamoya disease is a stenoocclusive disease involving the intracranial carotid and proximal middle cerebral arteries. There are rarely any additional extracranial stenoses occurring concurrently with moyamoya. The pathophysiology of moyamoya remains obscure, but hematologic disorders, notably sickle-cell anemia, have been associated in some cases. We describe the novel case of polycythemia vera associated with severe steno-occlusive disease of both intracranial and extracranial large arteries. A 47-year-old woman with polycythemia vera had multiple transient ischemic attacks, and noninvasive vessel imaging revealed steno-occlusive disease of bilateral supraclinoid internal carotid arteries with moyamoya-type collaterals, proximal left subclavian artery, right vertebral artery origin, bilateral renal arteries, superior mesenteric artery, and right common iliac artery. Laboratory workup for systemic vasculitis was negative. She required bilateral direct external carotid to internal carotid bypass procedures and percutaneous balloon angioplasty of her right VA origin stenosis. This case suggests that hematologic disorders can lead to vessel stenoses and occlusion. The pathophysiology may be due to a prothrombotic state leading to repeated endothelial injury, resultant intimal hyperplasia, and progressive steno-occlusion.

Abstract

Rapid assessment of adrenal function is critical following transsphenoidal surgery (TSS) for Cushing's disease (CD) in order to determine surgical efficacy. We hypothesize that there may be a role for ACTH measurement as a rapid indicator of adrenal function. Following surgery for CD, glucocorticoids were withheld and paired plasma ACTH and serum cortisol levels were measured every 6 h. Post-operative hypocortisolemia was defined as serum cortisol <2 mcg/dl or a serum cortisol <5 mcg/dl with the onset of symptoms of adrenal insufficiency within 72 h. We studied 12 subjects, all female, mean age 44.6 years (range 25-55), including 13 surgeries: nine subjects attained hypocortisolemia. Plasma ACTH levels decreased more in subjects with hypocortisolemia (0.9 pg/ml/hr, P = 0.0028) versus those with persistent disease (0 0.2 pg/ml/hr, P = 0.26) within the first 48 h after surgery. In contrast to subjects with persistent disease, all subjects with hypocortisolemia achieved a plasma ACTH <20 pg/ml by 19 h (range 1-19 h). Four of the nine subjects with hypocortisolemia achieved plasma ACTH <20 pg/ml by 13 h and the remaining five subjects by 19 h. Hypocortisolemia occurred between 3-36 h following achievement of a plasma ACTH <20 pg/ml. In CD, a reduction in postoperative plasma ACTH levels differentiates subjects with surgical remission versus subjects with persistent disease. The utility of plasma ACTH measurements in the postoperative management of CD remains to be determined.

Abstract

The role of stereotactic radiosurgery in the treatment of benign intracranial lesions is well established. Although a growing body of evidence supports its role in the treatment of malignant spinal lesions, a much less extensive dataset exists for treatment of benign spinal tumors.To examine the safety and efficacy of stereotactic radiosurgery for treatment of benign, intradural extramedullary spinal tumors.From 1999 to 2008, 87 patients with 103 benign intradural extramedullary spinal tumors (32 meningiomas, 24 neurofibromas, and 47 schwannomas) were treated with stereotactic radiosurgery at Stanford University Medical Center. Forty-three males and 44 females had a median age of 53 years (range, 12-86). Twenty-five patients had neurofibromatosis. Treatment was delivered in 1 to 5 sessions (median, 2) with a mean prescription dose of 19.4 Gy (range, 14-30 Gy) to an average tumor volume of 5.24 cm (range, 0.049-54.52 cm).After a mean radiographic follow-up period of 33 months (range, 6-87), including 21 lesions followed for ? 48 months, 59% were stable, 40% decreased in size, and a single tumor (1%) increased in size. Clinically, 91%, 67%, and 86% of meningiomas, neurofibromas, and schwannomas, respectively, were symptomatically stable to improved at last follow-up. One patient with a meningioma developed a new, transient myelopathy at 9 months, although the tumor was smaller at last follow-up.As a viable alternative to microsurgical resection, stereotactic radiosurgery provides safe and efficacious long-term control of benign intradural, extramedullary spinal tumors with a low rate of complication.

Abstract

IA is a valuable adjunct during surgery for a variety of neurovascular diseases; however, there are no reported series describing IA for DAVFs. This study was undertaken to evaluate the safety and efficacy of IA for DAVFs.A retrospective review of DAVF surgical cases during a 20-year period was conducted, and cases with IA were evaluated. Clinical details, surgical and angiographic findings, and postoperative outcomes were reviewed. The incidence of residual fistula on IAs, the utility of the surgical procedure, and the incidence of false-negative findings on IA were also determined.IA was performed in 29 patients (31 DAVFs) for DAVFs. The distribution of the fistulas was the following: transverse-sigmoid (n = 9), tentorial (n = 6), torcular (n = 3), cavernous sinus (n = 4), SSS (n = 4), foramen magnum (n = 3), and temporal-middle fossa (n = 2). Twelve patients had undergone prior embolization, while 6 patients had unsuccessful embolization procedures. Thirty-eight surgeries were performed for DAVF in 29 patients, and IA was performed in 34 surgeries. Forty-four angiographic procedures were performed in the 34 surgeries. Nine patients underwent multiple angiographies. In 11 patients (37.9%), IA revealed residual fistula after the surgeon determined that no lesion remained. This led to further exploration at the same sitting in 10 patients, while in 1 patient, further surgery was performed at a later date. False-negative findings on IA occurred in 3 patients (10.7%).IA is an important adjunct in surgery for DAVF. In this series, it resulted in further surgical treatment in 37.9% of patients. However, there was a 10% false-negative rate, which justified subsequent postoperative angiography.

Abstract

To integrate three-dimensional (3D) digital rotation angiography (DRA) and two-dimensional (2D) digital subtraction angiography (DSA) imaging into a targeting methodology enabling comprehensive image-guided robotic radiosurgery of arteriovenous malformations (AVMs).DRA geometric integrity was evaluated by imaging a phantom with embedded markers. Dedicated DSA acquisition modes with preset C-arm positions were configured. The geometric reproducibility of the presets was determined, and its impact on localization accuracy was evaluated. An imaging protocol composed of anterior-posterior and lateral DSA series in combination with a DRA run without couch displacement between acquisitions was introduced. Software was developed for registration of DSA and DRA (2D-3D) images to correct for: (a) small misalignments of the C-arm with respect to the estimated geometry of the set positions and (b) potential patient motion between image series. Within the software, correlated navigation of registered DRA and DSA images was incorporated to localize AVMs within a 3D image coordinate space. Subsequent treatment planning and delivery followed a standard image-guided robotic radiosurgery process.DRA spatial distortions were typically smaller than 0.3 mm throughout a 145-mm × 145-mm × 145-mm volume. With 2D-3D image registration, localization uncertainties resulting from the achievable reproducibility of the C-arm set positions could be reduced to about 0.2 mm. Overall system-related localization uncertainty within the DRA coordinate space was 0.4 mm. Image-guided frameless robotic radiosurgical treatments with this technique were initiated.The integration of DRA and DSA into the process of nidus localization increases the confidence with which radiosurgical ablation of AVMs can be performed when using only an image-guided technique. Such an approach can increase patient comfort, decrease time pressure on clinical and technical staff, and possibly reduce the number of cerebral angiograms needed for a particular patient.

Abstract

Moyamoya disease (MMD) is an idiopathic progressive arteriopathy affecting the proximal intracranial vasculature. To date only 4 case reports on intracranial angioplasty or stenting as treatment of this disease exist. We present 5 adult patients with MMD who failed angioplasty and/or stenting who remained symptomatic despite endovascular treatment or presented with recurrent symptoms and recurrence of stenosis/occlusion on angiography requiring subsequent extracranial-intracranial revascularization.Five adult MMD patients who underwent endovascular treatment with angioplasty or stenting were referred for further evaluation and treatment from outside hospitals. Data were collected from clinical referral notes and angiograms or reports. All patients underwent repeat 6-vessel cerebral angiography to assess the extent of disease and results of prior endovascular treatment.Six endovascular procedures were performed in all 5 patients. Internal carotid artery (ICA) balloon angioplasty and Wingspan stenting was performed in 2 patients (3 arteries). One patient had ICA-M1 angioplasty without stenting. Two patients had M1 angioplasty and Wingspan stenting. All patients developed repeat transient ischemic attacks following treatment attributable to the vascular territories of endovascular treatment. Repeat endovascular treatment was performed in 3 patients at a mean of 4 months (range = 2-6). Two went on to a third endovascular treatment due to progression of disease in the angioplastied/stented vessel. The average time of symptom recurrence after initial endovascular therapy was 1.8 months (0-4 months). Follow-up angiography when referred to our institution demonstrated 70-90% instent restenosis of the stented vessel in 3 and occlusion in 1 patient. Due to persistence of symptoms cerebral revascularization was performed in all patients.MMD is a progressive angiopathy. Angioplasty and stenting may temporarily improve the cerebral blood flow and decrease cerebral ischemic events but do not appear to be durable nor provide long-term prevention against future ischemic events.

Abstract

A case is reported of frameless image guided robotic radiosurgery for an arteriovenous malformation (AVM). C-arm CT (CACT) and concurrent digital subtraction angiography images were used for AVM localization within the CACT volume. Treatment planning was performed on CT images registered with the CACT dataset. During delivery, a robotic linear accelerator tracked the target based on localization with frequent stereoscopic x-ray imaging. This case demonstrates that a frameless approach to AVM radiosurgery is possible.

Abstract

The authors describe the case of a 13-year-old boy who presented with an intraventricular hemorrhage caused by a left trigonal arteriovenous malformation. After an initial recovery, the patient experienced complete right-sided paresis on posthemorrhage Day 6. Severe cerebral vasospasm was found on MR angiography and confirmed on conventional cerebral angiography. Intraarterial nicardipine injection and balloon angioplasty were successfully performed with improved vasospasm and subsequent neurological recovery. Cerebral vasospasm should be considered in the differential diagnosis for neurological deterioration following an arteriovenous malformation hemorrhage, and aggressive treatment can be administered to prevent ischemia and further neurological deficits.

Abstract

To determine the effectiveness and safety of image-guided robotic radiosurgery for spinal metastases.From 1996 to 2005, 74 patients with 102 spinal metastases were treated using the CyberKnife at Stanford University. Sixty-two (84%) patients were symptomatic. Seventy-four percent (50/68) of previously treated patients had prior radiation. Using the CyberKnife, 16-25 Gy in 1-5 fractions was delivered. Patients were followed clinically and radiographically for at least 3 months or until death.With mean follow-up of 9 months (range 0-33 months), 36 patients were alive and 38 were dead at last follow-up. No death was treatment related. Eighty-four (84%) percent of symptomatic patients experienced improvement or resolution of symptoms after treatment. Three patients developed treatment-related spinal injury. Analysis of dose-volume parameters and clinical parameters failed to identify predictors of spinal cord injury.Robotic radiosurgery is effective and generally safe for spinal metastases even in previously irradiated patients.

Abstract

Microsurgical resection of benign intradural extramedullary spinal tumors is generally safe and successful, but patients with neurofibromatosis, recurrent tumors, multiple lesions, or medical problems that place them at higher surgical risk may benefit from alternatives to surgery. In this prospective study, we analyzed our preliminary experience with image-guided radiosurgical ablation of selected benign spinal neoplasms.Since 1999, CyberKnife (Accuray, Inc., Sunnyvale, CA) radiosurgery was used to manage 51 patients (median age, 46 yr; range, 12-86 yr) with 55 benign spinal tumors (30 schwannomas, nine neurofibromas, 16 meningiomas) at Stanford University Medical Center. Total treatment doses ranged from 1600 to 3000 cGy delivered in consecutive daily sessions (1-5) to tumor volumes that varied from 0.136 to 24.6 cm.Less than 1 year postradiosurgery, three of the 51 patients in this series (one meningioma, one schwannoma, and one neurofibroma) required surgical resection of their tumor because of persistent or worsening symptoms; only one of these lesions was larger radiographically. However, 28 of the 51 patients now have greater than 24 months clinical and radiographic follow-up. After a mean follow-up of 36 months, all of these later lesions were either stable (61%) or smaller (39%). Two patients died from unrelated causes. Radiation-induced myelopathy appeared 8 months postradiosurgery in one patient.Although more patients studied over an even longer follow-up period are needed to determine the long-term efficacy of spinal radiosurgery for benign extra-axial neoplasms, short-term clinical benefits were observed in this prospective analysis. The present study demonstrates that CyberKnife radiosurgical ablation of such tumors is technically feasible and associated with low morbidity.

Abstract

It has been demonstrated by numerous studies that apoptotic cell death pathways are implicated in ischemic cerebral injury in ischemia models in vivo. Experimental ischemia and reperfusion models, such as transient focal/global ischemia in rodents, have been thoroughly studied and the numerous reports suggest the involvement of cell survival/death signaling pathways in the pathogenesis of apoptotic cell death in ischemic lesions. In these models, reoxygenation during reperfusion provides oxygen as a substrate for numerous enzymatic oxidation reactions and for mitochondrial oxidative phosphorylation to produce adenosine triphosphate. Oxygen radicals, the products of these biochemical and physiological reactions, are known to damage cellular lipids, proteins, and nucleic acids and to initiate cell signaling pathways after cerebral ischemia. Genetic manipulation of intrinsic antioxidants and factors in the signaling pathways has provided substantial understanding of the mechanisms involved in cell death/survival signaling pathways and the role of oxygen radicals in ischemic cerebral injury. Future studies of these pathways could provide novel therapeutic strategies in clinical stroke.

Abstract

The endoplasmic reticulum (ER), which plays a role in apoptosis, is susceptible to oxidative stress. Because superoxide is produced in the brain after ischemia/reperfusion, oxidative injury to this organelle may be implicated in ischemic neuronal cell death. Activating transcription factor-4 (ATF-4) and C/EBP-homologous protein (CHOP), both of which are involved in apoptosis, are induced by severe ER stress. Using wild-type and human copper/zinc superoxide dismutase transgenic rats, we observed induction of these molecules in the brain after global cerebral ischemia and compared them with neuronal degeneration. In ischemic, wild-type brains, expression of ATF-4 and CHOP was increased in the hippocampal CA1 neurons that would later undergo apoptosis. Transgenic rats had a mild increase in ATF-4 and CHOP and minimal neuronal degeneration, indicating that superoxide was involved in ER stress-induced cell death. We further confirmed attenuation on induction of these molecules in transgenic mouse brains after focal ischemia. When superoxide was visualized with ethidium, signals for ATF-4 and superoxide overlapped in the same cells. Moreover, lipids in the ER were robustly peroxidized by ischemia but were attenuated in transgenic animals. This indicates that superoxide attacked and damaged the ER, and that oxidative ER damage is implicated in ischemic neuronal cell death.

Abstract

The Ca2+-binding protein recoverin may regulate visual transduction in retinal rods and cones, but its functional role and mechanism of action remain controversial. We compared the photoresponses of rods from control mice and from mice in which the recoverin gene was knocked out. Our analysis indicates that Ca2+-recoverin prolongs the dark-adapted flash response and increases the rod's sensitivity to dim steady light. Knockout rods had faster Ca2+ dynamics, indicating that recoverin is a significant Ca2+ buffer in the outer segment, but incorporation of exogenous buffer did not restore wild-type behavior. We infer that Ca2+-recoverin potentiates light-triggered phosphodiesterase activity, probably by effectively prolonging the catalytic activity of photoexcited rhodopsin.

Abstract

Oxidative damage to the endoplasmic reticulum (ER) could be involved in ischemic neuronal cell death because this organelle is susceptible to reactive oxygen species. Using wild-type mice and copper/zinc-superoxide dismutase (SOD1) transgenic mice, we induced focal cerebral ischemia and compared neuronal degeneration and ER stress, that is, phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) and RNA-dependent protein kinase-like ER eIF2alpha kinase (PERK). We found that neurons with severe and prolonged phosphorylation of eIF2alpha and PERK underwent later degeneration, and that this was partially prevented by SOD1 overexpression. Signals for superoxide production and phospho-PERK were colocalized, which further indicates a pivotal role for superoxide in ER damage. We investigated the molecular mechanisms of oxidative ER stress and found that detachment of glucose-regulated protein 78 from PERK was the key step. We conclude that ER damage is involved in oxidative neuronal injury in the brain after ischemia/reperfusion.

Abstract

The endoplasmic reticulum (ER), which plays important roles in apoptosis, is susceptible to oxidative stress. Because reactive oxygen species (ROS) are robustly produced in the ischemic brain, ER damage by ROS may be implicated in ischemic neuronal cell death. We induced global brain ischemia on wild-type and copper/zinc superoxide dismutase (SOD1) transgenic rats and compared ER stress and neuronal damage. Phosphorylated forms of eukaryotic initiation factor 2 alpha (eIF2 alpha) and RNA-dependent protein kinase-like ER eIF2 alpha kinase (PERK), both of which play active roles in apoptosis, were increased in hippocampal CA1 neurons after ischemia but to a lesser degree in the transgenic animals. This finding, together with the finding that the transgenic animals showed decreased neuronal degeneration, indicates that oxidative ER damage is involved in ischemic neuronal cell death. To elucidate the mechanisms of ER damage by ROS, we analyzed glucose-regulated protein 78 (GRP78) binding with PERK and oxidative ER protein modification. The proteins were oxidatively modified and stagnated in the ER lumen, and GRP78 was detached from PERK by ischemia, all of which were attenuated by SOD1 overexpression. We propose that ROS attack and modify ER proteins and elicit ER stress response, which results in neuronal cell death.

Abstract

Prepontine arachnoid cysts are rare developmental anomalies that occur almost exclusively in children. The symptomatic child typically suffers from hydrocephalus, visual impairment, endocrine dysfunction and/or cranial neuropathies. Some cysts, however, are discovered incidentally upon prenatal or postnatal imaging for other indications. While there is little doubt that surgical treatment should be initiated to help the symptomatic child, appropriate therapy for the asymptomatic patient is unclear. Although arachnoid cysts are often managed conservatively using serial imaging, the consequences of injury to surrounding structures with prepontine cysts often lowers the threshold for intervention. The natural history of asymptomatic prepontine arachnoid cysts is unknown. It has been reported that some cysts enlarge and cause symptoms, whereas others are stable for years. This report describes an index case of spontaneous resolution of a prepontine arachnoid cyst in a female infant over a 5-year period.

Abstract

Arrestins are soluble cytoplasmic proteins that bind to G-protein-coupled receptors, thus switching off activation of the G protein and terminating the signalling pathway that triggers the cellular response. Although visual arrestin has been shown to quench the catalytic activity of photoexcited, phosphorylated rhodopsin in a reconstituted system, its role in the intact rod cell remains unclear because phosphorylation alone reduces the catalytic activity of rhodopsin. Here we have recorded photocurrents of rods from transgenic mice in which one or both copies of the arrestin gene were disrupted. Photoresponses were unaffected when arrestin expression was halved, indicating that arrestin binding is not rate limiting for recovery of the rod photoresponse, as it is in Drosophila. With arrestin absent, the flash response displayed a rapid partial recovery followed by a prolonged final phase. This behaviour indicates that an arrestin-independent mechanism initiates the quench of rhodopsin's catalytic activity and that arrestin completes the quench. The intensity dependence of the photoresponse in rods lacking arrestin further suggests that, although arrestin is required for normal signal termination, it does not participate directly in light adaptation.

Abstract

Although a given retina typically contains several visual pigments, each formed from a retinal chromophore bound to a specific opsin protein, single photoreceptor cells have been thought to express only one type of opsin. This design maximizes a cell's sensitivity to a particular wavelength band and facilitates wavelength discrimination in retinas that process color. We report electrophysiological evidence that the ultraviolet-sensitive cone of salamander violates this rule. This cell contains three different functional opsins. The three opsins could combine with the two different chromophores present in salamander retina to form six visual pigments. Whereas rods and other cones of salamander use both chromophores, they appear to express only one type of opsin per cell. In visual pigment absorption spectra, the bandwidth at half-maximal sensitivity increases as the pigment's wavelength maximum decreases. However, the bandwidth of the UV-absorbing pigment deviates from this trend; it is narrow like that of a red-absorbing pigment. In addition, the UV-absorbing pigment has a high apparent photosensitivity when compared with that of red- and blue-absorbing pigments and rhodopsin. These properties suggest that the mechanisms responsible for spectrally tuning visual pigments separate two absorption bands as the wavelength of maximal sensitivity shifts from UV to long wavelengths.